WO1992003404A1 - Procede de transformation de l'acide (benzoyl-3 phenyl)-2 propionique-r(-) en isomere s(+) - Google Patents

Procede de transformation de l'acide (benzoyl-3 phenyl)-2 propionique-r(-) en isomere s(+) Download PDF

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Publication number
WO1992003404A1
WO1992003404A1 PCT/FR1991/000670 FR9100670W WO9203404A1 WO 1992003404 A1 WO1992003404 A1 WO 1992003404A1 FR 9100670 W FR9100670 W FR 9100670W WO 9203404 A1 WO9203404 A1 WO 9203404A1
Authority
WO
WIPO (PCT)
Prior art keywords
ketoprofen
process according
base
mole
cinchonidine
Prior art date
Application number
PCT/FR1991/000670
Other languages
English (en)
French (fr)
Inventor
Claude Bertrand
Elie Fouque
Isidore Le Fur
Jean-Paul Richard
Original Assignee
Rhone-Poulenc Rorer S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone-Poulenc Rorer S.A. filed Critical Rhone-Poulenc Rorer S.A.
Priority to JP03514356A priority Critical patent/JP3100059B2/ja
Priority to EP91914913A priority patent/EP0544740B1/fr
Priority to DE69102767T priority patent/DE69102767T2/de
Publication of WO1992003404A1 publication Critical patent/WO1992003404A1/fr
Priority to NO930546A priority patent/NO179001C/no
Priority to FI930751A priority patent/FI101880B1/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification

Definitions

  • the present invention relates to a process for transforming the acid (3-benzoyl-phenyl) -2-propionic-R (-) into the SU isomer).
  • Propionic (3-benzoyl-phenyl) -2 (or ketoprofen) acid has particularly advantageous anti-inflammatory, analgesic and / or antipyretic properties.
  • Ketoprofen in racemic form, consists of an equimolecular mixture of the S (+) and R (-) enantiomers.
  • ketoprofen-S (+) [ketoprofen-S (+)], it has been shown that, in humans, ketoprofen-S (+) constitutes the active form of ketoprofen and that the R (-) isomer is not converted into S (+) isomer.
  • ketoprofen-SU practically free of the R (-) isomer.
  • Ketoprofen-SU can be obtained by splitting the racemic ketoprofen either by physicochemical methods (high performance liquid chromatography with a chiral phase) or by formation of a salt with an optically active base.
  • ketoprofen-R (-) can be transformed either in situ during the resolution of racemic ketoprofen by using in particular the agent of splitting as a transformation agent either from the splitting filtrates, after having possibly eliminated the chiral base, by treatment with a strong base. Soda can be used as a strong base.
  • the process is carried out in situ using as a splitting agent a chiral base such as cinchonidine and as solvent a ketone, such as methyl isobutyl ketone or an alcohol such as ethanol.
  • a chiral base such as cinchonidine
  • solvent such as a ketone
  • methyl isobutyl ketone which makes it possible to operate at high temperatures.
  • ketoprofen Generally, one mole of cinchonidine is used per mole of ketoprofen.
  • reduced pressure concentration is adjusted so that the temperature is constant and boiling around 100 C C throughout the duration of the concentration.
  • the crystals of the ketoprofen-S (+) salt which are formed are separated by hot filtration.
  • the transformation can also be carried out independently of the crystallization from the mother liquors of crystallization after having eliminated the chiral base used as a resolution agent using an achiral base such as sodium hydroxide.
  • the racemic ketoprofen is first split using 0.5 to 1 mole of cinchonidine per mole of ketoprofene.
  • ketoprofen mainly ketoprofen-S (+)
  • the mother liquors are treated with an aqueous solution of a strong mineral base such as sodium hydroxide after release and separation of the cinchonidine either as a base or as a salt.
  • Ketoprofen (mainly ketoprofen-R (-)), in the form of sodium salt, remains in basic aqueous solution which is heated to a temperature generally higher than 100 ⁇ C, preferably close to 110 ⁇ C according to the evolution of the optical titre as a function of time, the optical titre being expressed by the ratio 100 x R / (R + S).
  • the transformation is characterized by a gradual decrease in the optical titre.
  • Example 1 Duplication - Racemization
  • the yield is 58.6%.
  • ketoprofen The assessment on ketoprofen leads to the following results:
  • ketoprofen-R (-) 1.4 g (0.002 mole).
  • the yield is 53.6%.
  • the filtrates have the following composition:
  • ketoprofen-SU 2.5 g (0.010 mole)
  • ketoprofen-R (-) 4.5 g (0.018 mole)
  • the ethanolic solution is concentrated under reduced pressure (80 mm of mercury; 10.7 kPa) at 30 ⁇ C until a thick mass is obtained to which 57.7 liters (50 kg) of toluene are added and then still distills 20 liters of solvent.
  • the organic phase is washed with 35 liters of distilled water containing 1.5 liters of 9.8N hydrochloric acid and then with 30 liters of distilled water. The washes are discarded.
  • reaction mixture consists of 3 phases:
  • Cyclohexane is added to the concentrated toluene solution, heated to 70 ° C., such that the cyclohexane-toluene ratio is 6-4 (w / w) or 23 liters of cyclohexane.
  • the slurry After cooling to a temperature in the region of 15 ⁇ C, the slurry is filtered and then washed twice with a mixture of 3.5 liters of toluene and 6 liters of cyclohexane.
  • a filtration cake is thus obtained which represents 9.76 kg of dry ketoprofen and which is used as it is in a new splitting operation.
  • ketoprofen determined by non-chiral HPLC, is 100 X.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Detergent Compositions (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/FR1991/000670 1990-08-20 1991-08-19 Procede de transformation de l'acide (benzoyl-3 phenyl)-2 propionique-r(-) en isomere s(+) WO1992003404A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP03514356A JP3100059B2 (ja) 1990-08-20 1991-08-19 ［ｒ（−）］―２―（３―ベンゾイルフエニル）プロピオン酸をそのｓ（＋）異性体に変換する方法
EP91914913A EP0544740B1 (fr) 1990-08-20 1991-08-19 Procede de transformation de l'acide (benzoyl-3 phenyl)-2 propionique-r(-) en isomere s(+)
DE69102767T DE69102767T2 (de) 1990-08-20 1991-08-19 Verfahren zur umsetzung der r(-)(benzoyl-3 phenyl)-2 propionsäure zum isomer s(+).
NO930546A NO179001C (no) 1990-08-20 1993-02-16 Fremgangsmåte for omdanning av 2(3-benzoylfenyl) R(-)propionsyre til en S(+)isomer
FI930751A FI101880B1 (fi) 1990-08-20 1993-02-19 Menetelmä R(-) 2-(3-bentsoyylifenyyli)propionihapon muuttamiseksi S(+)-isomeeriksi

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9010460A FR2665897B1 (fr) 1990-08-20 1990-08-20 Procede de transformation de l'acide (benzoyl-3 phenyl)-2 propionique-r(-) en isomere s(+).
FR90/10460 1990-08-20

Publications (1)

Publication Number Publication Date
WO1992003404A1 true WO1992003404A1 (fr) 1992-03-05

Family

ID=9399732

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1991/000670 WO1992003404A1 (fr) 1990-08-20 1991-08-19 Procede de transformation de l'acide (benzoyl-3 phenyl)-2 propionique-r(-) en isomere s(+)

Country Status (19)

Country Link
EP (1) EP0544740B1 (cs)
JP (1) JP3100059B2 (cs)
AT (1) ATE108172T1 (cs)
AU (1) AU8445691A (cs)
CA (1) CA2089558A1 (cs)
CS (1) CS256791A3 (cs)
DE (1) DE69102767T2 (cs)
DK (1) DK0544740T3 (cs)
ES (1) ES2056657T3 (cs)
FI (1) FI101880B1 (cs)
FR (1) FR2665897B1 (cs)
HU (1) HUT63373A (cs)
IE (1) IE64689B1 (cs)
NO (1) NO179001C (cs)
NZ (1) NZ239435A (cs)
PL (1) PL297972A1 (cs)
PT (1) PT98726B (cs)
WO (1) WO1992003404A1 (cs)
ZA (1) ZA916496B (cs)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992018455A1 (en) * 1991-04-15 1992-10-29 Ethyl Corporation Resolution of ketoprofen

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023759A1 (fr) * 1995-01-31 1996-08-08 Nagase & Company, Ltd. Procede de racemisation d'acides carboxyliques a activite optique
US6459878B1 (en) 1999-09-30 2002-10-01 Canon Kabushiki Kaisha Heating assembly, image-forming apparatus, and process for producing silicone rubber sponge and roller
CN102010327B (zh) * 2009-09-07 2013-04-10 浙江九洲药业股份有限公司 (±)-2-(3-苯甲酰基)-苯基丙酸的拆分方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR296M (fr) * 1959-06-20 1960-08-26 Claude Marie Médicament hypoazotémique et hypocholestérolémiant.
GB2154233A (en) * 1984-02-16 1985-09-04 Stabil Bioterapico Farmachim Aluminium salts of arylalkanoic acids and pharmaceutical compositions containing them
US4831147A (en) * 1988-07-05 1989-05-16 The Dow Chemical Company Resolution of enantiomers of herbicidal 2-(4-aryloxyphenoxy) propionates by chiral two-phase extraction
EP0362476A2 (de) * 1988-07-19 1990-04-11 Paz Arzneimittel- Entwicklungsgesellschaft Mbh Verfahren zur Trennung von Gemischen enantiomerer Arylpropionsäuren

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR296M (fr) * 1959-06-20 1960-08-26 Claude Marie Médicament hypoazotémique et hypocholestérolémiant.
GB2154233A (en) * 1984-02-16 1985-09-04 Stabil Bioterapico Farmachim Aluminium salts of arylalkanoic acids and pharmaceutical compositions containing them
US4831147A (en) * 1988-07-05 1989-05-16 The Dow Chemical Company Resolution of enantiomers of herbicidal 2-(4-aryloxyphenoxy) propionates by chiral two-phase extraction
EP0362476A2 (de) * 1988-07-19 1990-04-11 Paz Arzneimittel- Entwicklungsgesellschaft Mbh Verfahren zur Trennung von Gemischen enantiomerer Arylpropionsäuren

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992018455A1 (en) * 1991-04-15 1992-10-29 Ethyl Corporation Resolution of ketoprofen

Also Published As

Publication number Publication date
FR2665897A1 (fr) 1992-02-21
FI101880B (fi) 1998-09-15
FI930751A0 (fi) 1993-02-19
PT98726A (pt) 1992-07-31
DK0544740T3 (da) 1994-08-22
NO179001C (no) 1996-07-17
NO930546D0 (no) 1993-02-16
ATE108172T1 (de) 1994-07-15
ZA916496B (en) 1992-05-27
IE64689B1 (en) 1995-08-23
DE69102767T2 (de) 1994-10-27
EP0544740A1 (fr) 1993-06-09
AU8445691A (en) 1992-03-17
NO179001B (no) 1996-04-09
PL297972A1 (en) 1993-11-02
FI930751A (fi) 1993-02-19
HUT63373A (en) 1993-08-30
EP0544740B1 (fr) 1994-07-06
JPH06501683A (ja) 1994-02-24
CA2089558A1 (fr) 1992-02-21
NO930546L (no) 1993-02-16
HU9300469D0 (en) 1993-05-28
NZ239435A (en) 1993-04-28
IE912917A1 (en) 1992-02-26
FR2665897B1 (fr) 1994-03-18
ES2056657T3 (es) 1994-10-01
JP3100059B2 (ja) 2000-10-16
FI101880B1 (fi) 1998-09-15
DE69102767D1 (de) 1994-08-11
PT98726B (pt) 1999-01-29
CS256791A3 (en) 1992-03-18

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